This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In past studies the effectiveness of a prime-boost protocol using attenuated vesicular stomatitis virus (VSV) vectors expressing SHIV Env, Gab , and Pol proteins was compared to a VSV vector prime followed with a single boost with modified vaccinia Ankara (MVA) expressing the same SHIV proteins. This approach used an unrelated vector (MVA) to boost SHIV immunity. After challenge with SHIV89.6P, MVA- boosted animals controlled peak challenge viral loads to less than 2x106 copies/ml, significantly lower than in VSV-boosted animals, and lower than reported in other vaccine studies employing the same challenge. MVA-boosted animals have shown excellent preservation of CD4+T cells while 2 of 4 VSV-boosted animals showed significant loss of CD4+T cells. The improved protection in MVA-boosted animals correlates with stronger pre-challenge CD8+T cell responses to SHIV antigens and with stronger post-challenge SHIV neutralizing antibody production. We are continuing monitoring five animals that were given either VSV/VSV or VSV/MVA vaccines and challenged with SHIV89.6p in 2002 (VSV-4). All animals have had viral loads below detectable limits. These animals are being bled quarterly to follow protection which has persisted for over 5 years. VSV-6 is a study using all mamu A01* + rhesus macaques. The A01* is a controller gene for SIVmac infection. VSV-vector immunized MamuA01+ animals had lower virus loads compared to controls. New studies (VSV-7) have shifted the vector system from SIVmac251 based system to a SIVE660 vaccine and challenge system. The advantage of the E660 systems is that this strain of SIVsm is partially sensitive to neutralizing antibody, similar to HIV-1.